Principal Investigator/Program Director (Last, first, middle): Herndon, David, N. RESEARCH &RELATED Other Project Information 1. * Are Human Subjects Involved? l Yes m No 1.a. If YES to Human Subjects Is the IRB review Pending? m Yes l No IRB Approval Date: 09-15-2006 Exemption Number: 1 2 3 4 5 6 Human Subject Assurance Number 00002729 2. * Are Vertebrate Animals Used? m Yes l No 2.a. If YES to Vertebrate Animals Is the IACUC review Pending? m Yes m No IACUC Approval Date: Animal Welfare Assurance Number 3. * Is proprietary/privileged information m Yes l No included in the application? 4.a.* Does this project have an actual or potential impact on m Yes l No the environment? 4.b. If yes, please explain: 4.c. If this project has an actual or potential impact on the environment, has an exemption been authorized or an environmental assessment (EA) or environmental impact statement (EIS) been performed? m Yes m No 4.d. If yes, please explain: 5.a.* Does this project involve activities outside the U.S. or m Yes l No partnership with International Collaborators? 5.b. If yes, identify countries: 5.c. Optional Explanation: 6. * Project Summary/Abstract 8175-Abstract.pdf Mime Type: application/pdf 7. * Project Narrative 6352-ProjectNarrative.pdf Mime Type: application/pdf 8. Bibliography &References Cited 9092-LiteratureCited.pdf Mime Type: application/pdf 9. Facilities &Other Resources 7127-Resources.pdf Mime Type: application/pdf 10. Equipment Tracking Number: Other Information Page 5 OMB Number: 4040-0001 Expiration Date: 04/30/2008 Principal Investigator/Program Director (Last, first, middle): Herndon, David, N. ABSTRACT Massive burns are associated with a persistent and sustained hypermetabolic response characterized by elevated levels of circulating catecholamines, cytokines and cortisol, which cause muscle wasting, immunodeficiency, organ dysfunction and a delay in wound healing. Insulin and propranolol have demonstrated an activity in selected patients which ameliorates the responses to burn with minimal associated side effects. We hypothesize that during acute hospitalization, propranolol titrated to reduce heart rate by 20%, and/or treatment with insulin titrated to a dose to maintain blood glucose between 80-110 mg/dL will reduce cardiovascula work, infections and improve wound healing, muscle wasting, inflammation, and recovery in both children and adults with severe thermal injuries. The specific aims are: 1): Determine the mechanisms whereby insulin, propranolol or their combination (insulin plus propranolol) affect whole body and organ function on a clinical level. 1a) We will determine organ function and clinical outcome by measuring cardiovascular responses, hypermetabolism, hormonal profile, body composition, incidence of infection and sepsis and their alterations with insulin, propranolol, or their combination. 1b) Another major aim of the present study is to determine the effect of insulin, propranolol and their combination on mortality. 2) Determine the mechanisms whereby insulin, propranolol and their combination exert their effects in muscle, wound, and liver on a cellular level. The acute effects of these drugs on cardiac work, protein and fat kinetics, glucose levels, wound healing, and body composition will be analyzed using a randomized prospective design in which compared. In this application we propose that insulin in combination with propranolol will benefit burned patients more than either alone, by improving muscle protein build-up, maintaining organ function, promoting rapid wound healing, decreasing cardiac work, improving mitochondrial function, and decreasing infections. Project Description Page 6 Principal Investigator/Program Director (Last, first, middle): Herndon, David, N. Project Narrative Massive burns are associated with a persistent and sustained hypermetabolic response characterized by elevated levels of circulating catecholamines, cytokines and cortisol, which cause muscle wasting, immunodeficiency, organ dysfunction and a delay in wound healing. Insulin and propranolol have demonstrated an activity in selected patients which ameliorates the responses to burn with minimal associated side effects. We hypothesize that during acute hospitalization, propranolol titrated to reduce heart rate by 20%, and/or treatment with insulin titrated to a dose to maintain blood glucose between 80-110 mg/dL will reduce cardiovascular work, infections and improve wound healing, muscle wasting, inflammation, and recovery in both children and adults with severe thermal injuries. Project Description Page 7